WO2007033781A1

WO2007033781A1 - Process for preparing 2-arylcarbonyl compounds, 2-aryl esters and 2-arylnitriles and their heteroaromatic analogues

Info

Publication number: WO2007033781A1
Application number: PCT/EP2006/008862
Authority: WO
Inventors: Andreas Meudt; Sven Nerdinger; Bernd Lehnemann; Till Vogel; Victor Snieckus
Original assignee: Archimica Gmbh
Priority date: 2005-09-22
Filing date: 2006-09-12
Publication date: 2007-03-29
Also published as: US20080221350A1; DE102005045132A1; EP1937613A1

Abstract

Process for preparing compounds of the formula (III) by cross-coupling of enolizable carbonyl compounds, nitriles or their analogues of the formula (II) with substituted aryl or heteroaryl compounds of the formula (I) in the presence of a Brönsted base and of a catalyst or precatalyst containing a.) a transition metal, a complex, a salt or a compound of this transition metal from the group {V, Mn, Fe, Co, Ni, Rh, Pd, Ir, Pt}, and b.) at least one sulphonated phosphane ligand in a solvent or solvent mixture in accordance with scheme (1), Hal standing for fluorine, chlorine, bromine, iodine, alkoxy or a sulphonate group; X1-5 denote independently of one another carbon or nitrogen, or pairs of adjacent X and R, joined via a formal double bond, stand in unison for O, S, NH or NR’; Z stands for O, S, NR’’, NOR’’, NNR’’’R’’, or Z together with Y forms a CN group. Y can stand for a radical from the group {hydrogen, methyl, linear, branched C1-C20 alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl, optionally substituted alkoxy, aryloxy, heteroaryloxy, optionally substituted alkylthio, arylthio, heteroarylthio, optionally substituted dialkylamino, di(hetero)arylamino, alkyl(hetero)arylamino} and with R’, R’, R’’ or R’’ may form a ring.

Description

description

Process for the preparation of 2-arylcarbonyl compounds, 2-aryl esters and 2-aryl nitriles and their heteroaromatic analogs

In the 2-position aryl- or heteroaryl-substituted carbonyl compounds and nitriles are a common structural motif in natural products, physiologically active compounds and chemical precursors. However, their importance in modern organic synthesis is limited by limitations in the accessibility of these classes of compounds, especially if additional functionalities are included in the target structure. In particular, the selective linkage of functionalized aromatics or heteroaromatics with complex carbonyl compounds and their analogs still presents difficulties because the standard method for the 2-functionalization of carbonyl compounds and their analogues - the implementation of their enols or enolates with electrophiles - on haloaromatics or heteroaromatics is applicable only in exceptional cases, namely when strongly electron-withdrawing substituents are present, which favor a nucleophilic aromatic substitution (see, for example, March, Advanced Organic Chemistry, Chapter 13: Aromatic Nucleophilic Substitution, pp. 641-676). In addition, the necessary harsh reaction conditions with sensitive functionalities are usually incompatible.

Recent developments circumvent these difficulties by accomplishing the linkage of enolates with aryl or heteroaryl halides by means of Pd and Ni catalysts, respectively, in the presence of various ligands which prevent the otherwise dominant reductive elimination (Culkin, Hartwig, Acc. Chem Res. 2003, 36, 235-245). However, the currently known methods all still have procedural or economic disadvantages that significantly limit the scope of application. Among other things, there are high costs of the catalysts / ligands, high required loadings / catalyst concentrations and difficult separability of the catalyst from the final product to mention. The latter is also due, inter alia, to the fact that the ligands used hitherto are all largely non-polar and therefore preferably stay in the organic phase together with the metal in the case of aqueous work-ups. It would be highly desirable to have a process which can convert substituted carbonyl compounds or nitriles with haloaromatics or halogenated heteroaromatics into the corresponding 2-aryl- or 2-heteroaryl-substituted carbonyl or nitrile compounds, while simultaneously achieving very high yields, with very high yields low catalyst quantities and additionally characterized by simple separation of the ligand and the transition metal used from the product. As already mentioned, the synthesis methods published so far do not solve this problem satisfactorily, as will be further demonstrated by some examples:

Use of expensive ligands (eg P ¹ Bu ₃ , Hartwig et al., US Pat. No. 6072073) and complex isolation of the product by chromatography.

Use of ligands which are difficult to synthesize (ferrocene-based ligands, Hartwig et al., US Pat. No. 6057456), extensive isolation of the product by chromatography.

• complicated or difficult, often multistep ligand syntheses (Buchwald et al., WO0002887), complex isolation of the product by chromatography.

• The separation of the catalyst from the product is often difficult, since the products formed bind the transition metals quite effectively, but on the other hand, for pharmaceutical fine chemicals very low specification limits are observed (eg <10 or <5 ppm). In addition, the catalyst systems commonly used are highly active in various other reactions, so that even in subsequent stages unwanted side reactions can be catalyzed

The present process overcomes all of these problems and relates to a process for preparing 2-aryl or heteroarylcarbonyl (III) compounds by cross-coupling enolizable carbonyl compounds, nitriles and their analogs (II) with substituted aryl or heteroaryl compounds (I) , in the presence of a Bronsted base and a catalyst or precatalyst containing a.) a transition metal, a complex, salt or a compound of this transition metal from the group {V, Mn, Fe, Co, Ni, Cu, Rh, Pd, Ir, Pt}, and b.) At least one sulfonated phosphine ligand in a solvent or solvent mixture according to Scheme 1, The process according to the invention is characterized by the following advantages:

• High yields and very high selectivities are achieved with very low catalyst loadings

It uses simple and economically accessible sulfonated ligands (by sulfonation of commercially available or easily accessible ligands, eg: the according to US-A-5789623 easily and very economically accessible 2-hydroxy-2 ^' dialkylphosphinobiaryle can be by simple treatment with sulfuric acid in the corresponding The easy accessibility of the corresponding Oxaphosphorinchloride (eg., 10-chloro-10H-9-oxa-10-phosphaphenanthren) is overall a very simple and with good yields running two-stage reaction, which is characterized by very high flexibility, since a wide variety of radicals can easily be introduced at the phosphorus.)

The catalyst activities achieved by the process according to the invention are very high, since the ligand is present in the reaction mixture as an anion and thus has particular electronic effects.

• A fine-tuning of the electronic properties of the ligands according to the invention is possible by the possibility of different counterions (metal cations, substituted ammonium salts, etc.). Especially with doubly deprotonatable ligands, such as. As in sulfonated 2-hydroxy-2 ^' - dialkylphosphinobiphenylen, can be tailored very targeted to the particular requirements of a particular reaction here.

• Easy separation of the ligand and metal from the product by aqueous extraction, since due to the very high acidity / polarity of the sulfonated ligands these are preferably in the aqueous phase.

The reaction can also be carried out in protic solvents, e.g. Substituted alcohols are carried out, often with a positive influence on the selectivity / reactivity.

• The inventive method extended by the mentioned, additionally finely adjustable parameters, the scope of the previously known C ₁ C coupling technologies exceptionally

• Exceptional activity of sulfonated ligands / catalyst systems, which often causes rapid reactions and short reaction times

IIa IMa

EQUATION 1a

I IIb IUb

EQUATION 1 b

In Equation 1a and 1b, Hal is fluorine, chlorine, bromine, iodine, alkoxy or a sulfonate leaving group such as trifluoromethanesulfonate (triflate), nonafluorotrimethylmethanesulfonate (nonaflate), methanesulfonate, benzenesulfonate, para-toluenesulfonate, 2-naphthalenesulfonate, 3 Nitrobenzenesulfonate, 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 2, 4, 6-triisopropylbenzenesulfonate.

Xi_ ₅ independently represent carbon or nitrogen, or in each case two adjacent via a formal double bond connected to X, R | together represent O (furans), S (thiophenes), NH or NR ^' (pyrroles).

Preferred compounds of the formula (I) which can be reacted by the process according to the invention are e.g. Benzenes, pyridines, pyrimidines, pyrazines, pyridazines, furans, thiophenes, pyrroles, any N-substituted pyrroles or naphthalenes, quinolines, indoles, benzofurans, etc.

The radicals Ri _-5 are substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 20 carbon atoms, at optionally one or more hydrogen atoms are replaced by fluorine or chlorine or bromine, eg CF ₃ , substituted cyclic or acyclic alkyl groups, hydroxy, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, pentafluorosulfuranyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, thio, alkylthio, arylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, optionally substituted aminocarbonyl, CO ₂ ^" , alkyl- or aryloxycarbonyl, hydroxyalkyl, alkoxyalkyl, fluorine or chlorine, nitro, cyano, aryl- or alkylsulfone, aryl- or alkylsulfonyl} or two adjacent radicals R1-5 may together form an aromatic, heteroaromatic or aliphatic fused ring.

Z is O, S, NR '"(protected imine), NOR" ¹ (protected oxime), NNR ¹¹¹ R "" (double protected hydrazone) or Z together with Y is N (nitrile) (Equation 1b).

R ', R ", R" ¹ and R "" are each independently identical or different radicals from the group of {hydrogen, methyl, linear, branched _C1-C20 alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl or a non-reactive functional group, eg, carbonyl, carboxyl, N-substituted imine, or nitrile, or two or more substituents R 'form a ring together or with an adjacent substituent.

Y can be a radical from the group {hydrogen, methyl, linear, branched C 1 -C 20 -alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl, optionally substituted alkoxy, aryloxy, heteraryloxy, optionally substituted alkylthio, arylthio, Heteroarylthio, optionally substituted dialkylamino, di (hetero) arylamino,

Alkyl (hetero) arylamino} and can form a ring with R ', R ", R ¹ " or R "".

Typical examples of the compound (II) are thus enolizable ketones, aldehydes, N-substituted imines, thioketones, carboxylic acid esters, thiocarboxylic acid esters and nitriles.

As a catalyst according to the invention a transition metal, preferably on a support such as. As palladium on carbon, or a salt, a complex or a organometallic compound of this metal used. The transition metal is preferably selected from the following group {V, Mn, Fe, Co, Ni ₁ Cu, Rh ₁ Pd, Ir, Pt}, preferably palladium or nickel, with a sulfonated ligand.

The catalyst can be added in finished form or form in situ, e.g. from a precatalyst by reduction or hydrolysis or from a metal salt and added ligand by complex formation. The catalyst is used in combination with one or more, but at least one, sulfonated phosphorus ligand.

The metal can be used in any oxidation state. According to the invention, it is used in amounts of from 0.0001 mol% to 100 mol%, preferably between 0.01 and 10 mol%, particularly preferably between 0.01 and 1 mol%, in relation to the reactant (I).

Sulfonated phosphine ligands are used according to the invention, which are characterized in that preferably at least one sulfonic acid group or a salt of a sulfonic acid group is contained in the molecule.

Preferred are ligands of structure (IV) shown below

used in conjunction with transition metals, preferably palladium or nickel as a catalyst. XI _-5 are independently of each other carbon or nitrogen or each two adjacent via a formal double bond connected XjR ₁ with i = 2,3,4,5 together represent O (furan), S (thiophene), NH or NR, (pyrrole) ;

the radicals R _2- io correspond in their meaning to the radicals R _1-5 , where at least one of the radicals contains a sulfonic acid or sulfonate group.

R ^a and R ^b independently of one another denote identical or different radicals from the group {hydrogen, methyl, linear, branched or cyclic C 1 -C 20 -alkyl, optionally substituted, phenyl, optionally substituted} or together form a ring and represent a bridging structural element from the group {optionally substituted alkylene, branched alkylene, cyclic alkylene} or independently of one another for one or two polycyclic radicals, such as norbornyl or adamantyl.

Particular preference is given here to those derivatives which contain not only at least one sulfonic acid group but also another deprotonatable function in the molecule, such as. B. a free OH group in the sulfonated ring.

In a further preferred embodiment, complexes of a sulfonated secondary phosphine in combination with a palladacycle as the catalyst of the structure

used, wherein the symbols Xi-5, R2-9, R 'and R "have the abovementioned meaning and Y' is a radical from the group {halide, Pseudohalogeπid, alkyl carboxylate, trifluoroacetate, nitrate, nitrite} and R _c and R _d independently of one another are identical or different substituents from the group {hydrogen, methyl, primary, secondary or tertiary optionally substituted C 1 -C 20 -alkyl or aryl} or together form a ring and from the group {optionally substituted alkylene, Oxaalkylene, thiaalkylene, azaalkylene}, and at least one sulfonic acid group or sulfonate salt is contained in the secondary phosphine.

In a further preferred embodiment, complexes of a tertiary phosphine of the structure

(VI), where the symbols Xi-S, Ri-s and R 'have the abovementioned meaning, where n can denote 1, 2 or 3 and m = 3-n and n aryl or heteroaryl independently of one another may be the same or different nature, as well as the m radicals may be independently of the same or different nature, wherein at least one sulfonated aromatic ring is contained. Mixtures of different ligands of this class can be used.

Suitable catalysts or precatalysts for the process according to the invention are, for example, complexes of palladium or nickel with sulfonated biarylphosphines, some of which are very simple and economically accessible (for example, (VII) and (VIII), for the preparation see EP-A-0795559) or as a representative of the third type described, the commercially available sulfonated triphenyl phosphines (formulas ((IX ac) TPPTS, TPPDS and TPPMS. Y = HX = Y = H

(VII) (VIII) (IX)

The addition of Brønsted bases to the reaction mixture is necessary to achieve acceptable reaction rates. As bases are well suited for. As hydroxides, alcoholates and fluorides of alkali and alkaline earth metals, carbonates, bicarbonates, phosphates, amides and silazides of the alkali metals and their mixtures. Particularly suitable are the bases of the group {potassium tert-butoxide, sodium tert-butoxide, cesium tert-butylate, lithium tert-butoxide and the corresponding isopropylates, potassium hexamethyldisilazide, Natriumhexamethyldisilazid, Lithiumhexam methyldisilazid}.

In this case, usually at least the amount of base is used, which corresponds to the amount of substance to be coupled compound, usually 1, 0 to 6 equivalents, preferably 1, 2 to 3 equivalents of base based on the compound (II) used.

The reaction is carried out in a suitable solvent or a single- or multiphase solvent mixture which has a sufficient dissolving power for all participating reactants, wherein heterogeneous implementations are also possible (eg use of almost insoluble bases). Preferably, the reaction is carried out in polar, aprotic or protic solvents. Well suited are dimethylformamide (DMF), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), open-chain and cyclic ethers and diethers, oligo- and polyethers and substituted mono- or polyhydric alcohols and optionally substituted aromatics. Particular preference is given to one or mixtures of a plurality of solvents from the group {dimethylformamide (DMF), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), diglyme, substituted glymes, 1, 4-dioxane, isopropanol, tert-butanol, 2,2-dimethyl-1-propanol, toluene, xylene} used.

The reaction can be carried out at temperatures ranging from room temperature to the boiling point of the solvent used at the pressure used. To achieve a faster reaction, the implementation at elevated temperatures in the range of 0 to 240 ⁰ C is preferred. Particularly preferred is the temperature range of 10 to 200 ⁰ C, in particular from 20 to 150 ⁰ C.

The concentration of reactants (I) and (II) can be varied within wide limits. Conveniently, the reaction is carried out in the highest possible concentration, wherein the solubilities of the reactants and reagents must be observed in the particular reaction medium. Preferably, the reaction is carried out in the range of 0.05 to 5 mol / l based on the reactant present in the deficit (depending on the relative prices of the reactants).

The carbonyl derivative or analogue of the formula (II) and aromatic or heteroaromatic reaction partner (I) can be employed in molar ratios of from 10: 1 to 1:10, ratios of from 3: 1 to 1: 3 are preferred, and ratios are particularly preferred from 1.2: 1 to 1: 1.2.

In one of the preferred embodiments, all materials are initially charged and the mixture is heated with stirring to the reaction temperature. In another preferred embodiment, which is particularly suitable for large scale use, the compound (II) and optionally other reactants, e.g. Base and catalyst or pre-catalyst dosed during the reaction to the reaction mixture. Alternatively, it is also possible to perform metered-controlled by slow addition of the base.

The workup is usually carried out with a mixture of aromatic hydrocarbons / water with removal of the aqueous phase, which absorbs the inorganic constituents and ligand and transition metal, wherein the product remains in the organic phase, if not present acidic functional groups lead to a different phase behavior. If necessary, you can ionic liquids are used to separate the polar constituents. The product is preferably isolated by precipitation or distillation from the organic phase, for example by concentration or by addition of precipitants. In most cases, an additional purification or subsequent separation of transition metal or ligand z. B. by recrystallization or chromatography unnecessary.

The isolated yields are for ketones and their derivatives usually in the range of 60 to 100%, preferably in the range> 70% to 90%, for malonates and their derivatives usually in the range of 50-80%, preferably> 60% to 80%. The selectivities are very high according to the invention, it is usually possible to find conditions under which, with the exception of very small amounts of dehalogenation product, no further by-products can be detected.

The inventive method opens up a very economical method, especially in the workup and separation of catalyst / ligand to 2-position arylated or heteroarylated carbonyl compounds, their derivatives and analogues and nitriles starting from the corresponding carbonyl compounds or their derivatives and nitriles and the corresponding aryl or heteroaryl halides or sulfonates and generally provides the products in very high purities without expensive purification procedures.

The process according to the invention shall be illustrated by the following examples, without limiting the invention thereto:

Example 1 Preparation of the ligand 2'-hydroxy-2-dicyclohexylphosphino-biphenyl-4'-sulfonic acid (HBPNS)

1,099 g (3.0 mmol) of 2-hydroxy-2'-diphenylphosphinobiphenyl were precooled under an inert gas atmosphere in an ice bath. Subsequently, 2.0 ml of concentrated sulfuric acid were slowly added from a syringe. After warming to room temperature, the resulting suspension was stirred for a further ca. 2 hours until all the solid had dissolved. A homogeneous, viscous and slightly brownish-colored suspension was obtained. The reaction mixture was cooled again in an ice bath and then quenched with ice. With concentrated sodium hydroxide solution, the precipitate formed was completely dissolved. After dilution with 75 ml of water and acidification with 1 N sulfuric acid, the precipitate was filtered off and washed with water until the running wash water shows neutral pH. The white cake was washed once more with methanol and dried in vacuo. This gave 1093 g (2.45 mmol, 82%) of 2-hydroxy-2'-diphenylphosphinobiphenyl-5-sulfonic acid as white crystals.

Example 2: Coupling of 4-bromobenzonitrile with acetophenone to 4- (2-oxo-2-phenylethyl) benzonitrile

182 mg of 4-bromobenzonitrile (1 mmol) and 120 mg of acetophenone (1 mmol) were dissolved under inert gas in 5 ml of N, N-dimethylformamide and treated with 192 mg of sodium tert-butylate (2 mmol). Was allowed to stir for 15 min and was then 17.9 mg (4 mol%) of the HBPNS- ligand and 9.0 mg Pallad ium (II) acetate (4 mol%) is added and heated for 14.5 h at 80 ⁰ C. For working up, 5 ml Added water and 10 ml of toluene, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. The solvent was removed on a rotary evaporator in vacuo. 175 mg of the product were obtained (0.79 mmol, 79%).

Example 3 Coupling of 4-bromobenzonitrile with cyclohexanone to 4- (2-oxocyclohexyl) benzonitrile

182 mg of 4-bromobenzonitrile (1 mmol) and 98 mg of cyclohexanone (1 mmol) were dissolved in 5 ml of N, N-dimethylformamide under protective gas and treated with 192 mg of sodium tert-butylate (2 mmol). The mixture was stirred for 15 minutes and then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and the mixture was heated to 80 ^° C. for 14.5 h. 5 ml of water were used for the work-up and 10 ml of toluene, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. The solvent was removed on a rotary evaporator in vacuo. After flash chromatography (cyclohexane / ethyl acetate 10: 1), 111.6 mg of the product (0.56 mmol, 56%) were obtained. Example 4: Coupling of 4-bromoanisole with acetophenone to 2- (4-methoxyphenyl) -1-phenylethanone

187 mg of 4-bromoanisole (1 mmol) and 120 mg of acetophenone (1 mmol) were dissolved in 5 ml of N, N-dimethylformamide under protective gas and admixed with 192 mg of sodium tert-butylate (2 mmol). The mixture was stirred for 15 minutes and then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and the mixture was heated to 80 ^° C. for 14.5 h. 5 ml of water were used for the work-up and 10 ml of toluene, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. The solvent was removed on a rotary evaporator in vacuo. 185 mg of product (0.82 mmol, 82%) were obtained.

Example 5: Coupling of 4-bromoanisole with cyclohexanone to 2- (4-methoxyphenyl) -cyclohexanone

187 mg of 4-bromoanisole (1 mmol) and 98 mg of cyclohexanone (1 mmol) were dissolved in 5 ml of N, N-dimethylformamide under protective gas and admixed with 192 mg of sodium tert-butylate (2 mmol). The mixture was stirred for 15 minutes and then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and the mixture was heated to 80 ^° C. for 20 h. 5 ml of water were used for the work-up and 10 ml of toluene, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. The solvent was removed on a rotary evaporator in vacuo. After flash chromatography (cyclohexane / ethyl acetate 10: 1), 146 mg of the product (0.71 mmol, 71%) were obtained.

Example 6: Coupling of 4-chlorobromobenzene with diethyl malonate to diethyl 2- (4-chlorophenyl) malonate

191.5 mg of 4-chlorobromobenzene (1 mmol) and 160 mg of diethylmalonate (1 mmol) were dissolved under inert gas in 5 ml of N, N-dimethylformamide, with 652 mg of cesium carbonate (2 mmol) and stirred for 1 h. Then 17.9 mg (4 mol%) of the HBPNS

Added ligand and 9.0 mg of palladium (II) acetate (4 mol%) and heated to 80 ⁰ C for 24 h.

For workup, 5 ml of water and 10 ml of toluene were added, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. After removal of toluene on

Rotary evaporators gave 230 mg (0.85 mmol, 85%) of the product.

Example 7: Coupling of 4-chlorobromobenzene with ethyl cyanoacetate to ethyl 4-chlorophenylcyanoacetate

191.5 mg of 4-chlorobromobenzene (1 mmol) and 113 mg of ethyl cyanoacetate (1 mmol) were dissolved under inert gas in 5 ml of N, N-dimethylformamide, admixed with 652 mg of cesium carbonate (2 mmol) and stirred for 1 h. Then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and heated to 80 ^° C. for 24 h.

For workup, 5 ml of water and 10 ml of toluene were added, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. Removal of the toluene on a rotary evaporator gave 166 mg (0.74 mmol, 74%) of the product.

Example 8 Coupling of 4-chlorobromobenzene with malononitrile to 1-chloro-4-dicyanomethylbenzene

191.5 mg of 4-chlorobromobenzene (1 mmol) and 66 mg of malononitrile (1 mmol) were dissolved under protective gas in 5 ml of N, N-dimethylformamide, mixed with 343 mg of barium hydroxide (2 mmol) and stirred for 1 h. Then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and heated to 80 ^° C. for 24 h. For workup, 5 ml of water and 10 ml of toluene were added, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. Removal of the toluene on a rotary evaporator gave 149 mg (0.85 mmol, 85%) of the product. Example 9 Coupling of phenylacetic acid ethyl ester with 4-bromotoluene to phenyl-p-tolylacetic acid ethyl ester

164 mg of phenylacetic acid ethyl ester (1 mmol) and 171 mg of 4-bromotoluene (1 mmol) under protective gas at room temperature with 224 mg of potassium tert-butoxide (2 mmol) and stirred for 30 min then 17 9 mg (4 mol%) of HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) was added and heated for 3 h at 80 ⁰ C. For workup, 5 ml of water and 10 ml of toluene were added, shaken, drained the lower water phase and washed with 5 ml of water to remove remaining dimethylformamide After removal of toluene on a rotary evaporator and flash chromatography (cyclohexane / ethyl acetate 10 1) to 176 mg (0.69 mmol, 69%) of the product

Example 10 Coupling of 4-bromobenzonitrile with octanal to give 4- (1-formylheptyl) benzonitπl

182 mg of 4-Brombenzonιtril (1 mmol) and 128 mg of octanal (1 mmol) were dissolved under inert gas in 5 ml of N, N-Dιmethylformamιd and treated with 192 mg of sodium tert-butoxide (2 mmol). The mixture was stirred for 15 minutes and then 17 9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and the mixture was heated to 80 ° C. for 14.5 h. 5 ml of water were worked up for work-up and 10 ml of toluene, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. The solvent was removed in vacuo on a rotary evaporator. 136 mg of the product (0 57 mmol, 57%) were obtained.

Example 11 Coupling of 4-bromobenzonitrile with phenylacetaldehyde to give 4- (2-oxo-1-phenylethyl) benzonitrile

182 mg of 4-bromobenzonitrile (1 mmol) and 120 mg of phenylacetaldehyde (1 mmol) were dissolved under protective gas in 5 ml of N, N-dimethylformamide and 192 mg of sodium tert-butylate (2 mmol) were added. The mixture was stirred for 15 min and added then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) and heated to 80 ^° C. for 14.5 h.

For workup, 5 ml of water and 10 ml of toluene were added, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. The solvent was removed on a rotary evaporator in vacuo. 150 mg of product (0.65 mmol, 65%) were obtained.

Example 12: Coupling of 4-bromobenzotrifluoride with phenylacetonitrile to phenyl (4-trifluoromethyl) -acetonitrile

117 mg of phenylacetonitrile (1 mmol) and 225 mg of 4-bromobenzotrifluoride (1 mmol) were mixed under protective gas at room temperature with 224 mg of potassium tert-butoxide (2 mmol) and stirred for 30 min. Then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and heated to 80 ^° C. for 3.5 h. For workup, 5 ml of water and 10 ml of toluene were added, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. Removal of the toluene on a rotary evaporator and flash chromatography (cyclohexane / ethyl acetate 10: 1) gave 165 mg (0.76 mmol, 76%) of the product.

Example 13: Coupling of 4-bromobenzotrifluoride with isobutyronitrile to 2-methyl-2- (4-trifluoromethylphenyl) -propionitrile

69 mg of isobutyronitrile (1 mmol) and 225 mg of 4-bromobenzotrifluoride (1 mmol) were mixed under protective gas at room temperature with 334 mg of lithium hexamethyldisilazane (2 mmol) and stirred for 30 min. Then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and heated to 80 ^° C. for 10 h. For workup, 5 ml of water and 10 ml of toluene were added, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. After removal of toluene on Rotary evaporator and flash chromatography (cyclohexane / ethyl acetate 10: 1) gave 101 mg (0.55 mmol, 55%) of the product.

Example 14: Coupling of N-diphenylmethylenglycine ethyl ester with bromobenzene to 2-N-diphenylmethylene-2-aminophenylacetic acid

267 mg of N-Diphenylmethylenglycinethylester (1 mmol) and 157 mg of bromobenzene (1 mmol) were added under protective gas at room temperature with 224 mg of potassium tert-butoxide (2 mmol) and stirred for 30 min. Then 17.9 mg (4 mol%) of the HBPNS ligand and 9.0 mg of palladium (II) acetate (4 mol%) were added and heated to 80 ^D C for 24 h.

For workup, 5 ml of water and 10 ml of toluene were added, shaken, drained the lower water phase and washed to remove residual dimethylformamide again with 5 ml of water. Removal of the toluene on a rotary evaporator and flash chromatography (cyclohexane / ethyl acetate 10: 1) gave 282 mg (0.82 mmol, 82%) of the product.

Claims

claims:

1. A process for the preparation of compounds of formula (III) by cross-coupling of enolisable carbonyl compounds, nitriles or their analogs of formula (II) with substituted aryl or heteroaryl compounds of formula (I) ₁ in the presence of a Bronsted base and a catalyst or precatalyst containing a.) a transition metal, a complex, a salt or a compound of this transition metal from the group {V, Mn, Fe, Co, Ni, Rh, Pd, Ir, Pt}, and b.) at least one sulfonated phosphine ligand in one Solvent or solvent mixture according to Scheme 1,

I Il III

SCHEMA 1

wherein Hal is fluorine, chlorine, bromine, iodine, alkoxy or sulfoπatgruppe;

Xi _-5 independently represent carbon or nitrogen or each two adjacent XjRjs connected via a formal double bond together represent O, S, NH or NR ';

the radicals Ri _-5 stand for substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 20 C atoms, in which optionally one or more hydrogen atoms are replaced by fluorine or chlorine or bromine, cyclic or acyclic alkyl groups, hydroxy, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, pentafluorosulfuranyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, thio, alkylthio, arylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, aminocarbonyl, CO ₂ ^" , Alkyl or aryloxycarbonyl, hydroxyalkyl, alkoxyalkyl, fluorine or chlorine, nitro, cyano, Aryl or alkylsulfone, aryl or alkylsulfonyl} or two adjacent radicals R ^ s together form an aromatic, heteroaromatic or aliphatic fused ring,

Z is O, S, NR " ¹ , NOR '", NNR'"R""or Z together with Y is a CN group.

R ', R ", R'" and R "" stand for identical or different radicals from the group {hydrogen, methyl, linear, branched C ₁ -C ₂₀ alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl or a functional group not participating in the reaction, eg, carbonyl, carboxyl, N-substituted imine or nitrile}, or two substituents Ri together form a ring or with an adjacent substituent.

Y may be a radical from the group {hydrogen, methyl, linear, branched C ₁ -C 20 -alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl, optionally substituted alkoxy, aryloxy, heteraryloxy, optionally substituted alkylthio, Arylthio, heteroarylthio, optionally substituted dialkylamino, di (hetero) arylamino,

Alkyl (hetero) arylamino} and can form a ring with R ', R ", R" ¹ or R "".

2. The method according to claim 1, characterized in that sulfonated phosphine ligands are used which contain at least one sulfonic acid group or a metal sulfonate.

3. The method according to claim 1 and / or 2, characterized in that as Bronsted base an alcoholate or amide of the alkali or alkaline earth metals or an alkali carbonate or phosphate or silicide or mixtures of these compounds are used.

4. The method according to at least one of the preceding claims, characterized in that 1, 0 to 3 equivalents of base based on the aryl or heteroaryl or aryl or heteroaryl are used.

5. The method according to at least one of the preceding claims, characterized in that as solvents hydrocarbons, halogenated hydrocarbons, open-chain and cyclic ethers and diethers, oligo- and polyethers, tertiary amines, DMSO, NMP, DMF, DMAc and substituted single or multiple alcohols and optionally Substituted aromatics or a mixture of several of these solvents is used.

6. The method according to at least one of the preceding claims, characterized in that the reaction is carried out at a temperature in the range of 0 to 240 ⁰ C.

7. The method according to at least one of the preceding claims, characterized in that the catalyst in relation to the reactant (I) in amounts of 0.001 mol% to 100 mol% is used.

8. The method according to at least one of the preceding claims, characterized in that a phosphine ligand of the structure

is used, where

Xi _-5 are each independently carbon or nitrogen or each two adjacent via a formal double bond connected XjRi with i = 2,3,4,5 together represent O (furan), S (thiophene), NH or NRj (pyrrole);

the radicals R io _2- correspond in meaning the radicals Ri _-5, wherein at least one radical containing a sulfonic or sulfonate group; Ra and Rb independently of one another denote identical or different radicals from the group {hydrogen, methyl, linear, branched or cyclic C ₁ -C ₂₀ -alkyl, phenyl} or together form a ring and represent a bridging structural element from the group {alkylene, branched Alkylene, cyclic alkylene} or independently of one another for one or two polycyclic radicals.

9. The method according to at least one of the preceding claims, characterized in that as the phosphine ligand and catalyst, a complex of a sulfonated secondary phosphine in combination with a palladacycle of the formula (V)

(V)

is used, wherein the symbols X-us, R ₂ - ₉ , R 'and R "have the abovementioned meaning and Y' is a radical from the group {halide, pseudohalide, alkyl carboxylate, trifluoroacetate, nitrate, nitrite} and

R _c and R _d are each independently identical or different substituents from the group of {hydrogen, primary, secondary or tertiary, optionally substituted CrC _Σ Oalkyl or aryl methyl} or together form a ring and from the group of {optionally substituted alkylene, oxaalkylene Thiaalkylen, Azaalkylen} come from and at least one sulfonic acid group or a sulfonate salt in the secondary Phophan is included.

10. The method according to at least one of the preceding claims, characterized in that as a phosphine ligand a complex of a sulfonated tertiary phosphine of the formula (VI)

(VI) is used, wherein the symbols Xi _-5 , R _1-5 and R 'have the abovementioned meaning, where n can denote 1, 2 or 3 and m = 3-n, and the n aryl or heteroaryl and the m residues may be the same or different independently of each other, and mixtures of different ligands of this class may be employed.